Following his PhD, Markram went to the United States as a Fulbright Scholar at the National Institutes of Health (NIH), where he studied ion channels on synaptic vesicles. As a Minerva Fellow he then went to the Laboratory of Bert Sakmann at the Max Planck Institute, Heidelberg, Germany, where he discovered calcium transients in dendrites evoked by sub-threshold activity, and by single action potentials propagating back into dendrites. He also began studying the connectivity between neurons, describing in great detail how layer 5 pyramidal neurons are interconnected.

Some of his work altered the relative timing of single pre- and post-synaptic action potentials to reveal a learning mechanism operating between neurons where the relative timing in the millisecond range affects the coupling strength between neurons. The importance of such timing has been reproduced in many brain regions and is known as spike timing-dependent synaptic plasticity (STDP).[3]

Markram was appointed assistant professor at the Weizmann Institute of Science, where he started systematically dissecting out the neocortical column. He discovered that synaptic learning can also involve a change in synaptic dynamics (called redistribution of synaptic efficacy) rather than merely changing the strengths of connections. He also studied principles governing neocortical microcircuit structure, function, and emergent dynamics. Together with Wolfgang Maass[4] he developed the so-called theory of liquid state machine, or high entropy computing.

In 2002 he moved to EPFL as full professor and founder/director of the Brain Mind Institute and Director of the Center for Neuroscience and Technology. At the BMI, in the Laboratory for Neural Microcircuitry, Markram continues to study the organisation of the neocortical column, develops tools to carry out multi-neuron patch clamp recordings combined with laser and electrical stimulation as well as multi-site electrical recording, chemical imaging and gene expression.[3]